CN102124001A - Derivatives of 2-oxo-alkyl-1-piperazin-2-one, preparation method thereof and therapeutic use of same - Google Patents
Derivatives of 2-oxo-alkyl-1-piperazin-2-one, preparation method thereof and therapeutic use of same Download PDFInfo
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- CN102124001A CN102124001A CN2009801315538A CN200980131553A CN102124001A CN 102124001 A CN102124001 A CN 102124001A CN 2009801315538 A CN2009801315538 A CN 2009801315538A CN 200980131553 A CN200980131553 A CN 200980131553A CN 102124001 A CN102124001 A CN 102124001A
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Abstract
The invention relates to derivatives of 4-{2-[phenyl-3, 6- dihydro-pyridin-1-yl]-2-oxo-alkyl}-1-piperazin-2-one and 4-{2-[phenyl-2, 5-dihydro-pyrrol-1- yl]-2-oxo-alkyl}-1 -piperazin-2-one having general formula (I), wherein: A, B, m, R3 and n are as defined in claim 1. The invention also relates to the preparation thereof and to the therapeutic use of same.
Description
Technical field
The present invention relates to 4-{2-[phenyl-3,6-dihydropyridine-1-yl]-the 2-oxoalkyl group }-1-piperazine-2-ketone and 4-{2-[phenyl-2,5-pyrrolin-1-yl]-the 2-oxoalkyl group }-1-piperazine-2-ketone derivatives, relate to its preparation and therepic use thereof.
Compound of the present invention is to p75
NTRNeurotrophin (neurotrophine) acceptor has avidity.
Background technology
The biological action of the protein family under the neurotrophin is specially cell survival and differentiation.
P75
NTRAcceptor is the acceptor of all neurotrophins, be tumour necrosis factor (TNF) receptor family transmembrane glycoprotein (W.J.Friedman and L.A.Greene, Exp.Cell.Res., 1999,253,131-142).P75
NTRAcceptor is expressed in several cell types, and following several biological function is attributed to described acceptor: on the one hand, regulate the avidity of neurotrophin to Tyrosylprotein kinase (trk) acceptor; On the other hand, when trk does not exist, induce by apoptotic necrocytosis signal.And, the neurotrophin precursor, preceding neurotrophin (proneurotrophine) can be with high-affinity in conjunction with p75
NTR, and be regarded as p75 powerful in neurone and some clone
NTRDependent cell apoptosis induction thing.
In the level of central nervous system, many apoptosis that studies show that relate to several pathological states, for example amyotrophic lateral sclerosis, multiple sclerosis, alzheimer's disease, Parkinson's disease, Huntington Chorea and prion disease etc.Also known p75
NTRIn multiple neurodegenerative disease such as alzheimer's disease and amyotrophic lateral sclerosis (ALS), cross and express (Longo F.M. etc., Curr.Alzheimer Res.2007; 4:503-506; Lowry K.S. etc., Amyotroph.Lateral.Scler.Other.Motor.Neuron.Disord.2001; 2:127-34).
Result of study shows p75
NTRMay be after causing ischemic play a major role in the mechanism of apoptosis neuronal death (P.P.Roux etc., J.Neurosci., 1999,19,6887-6896).
Result of study (V.Della-Bianca etc., J.Biol.Chem., 2001,276:38929-33 and S.Rabizadeh etc., Proc.Natl.Acad.Sci.USA, 1994,91,10703-10706) supported p75
NTRThe hypothesis that in infection induced (propagated spongiform encephalopathy (transmissible spongiforn encephalopathy)) of prion protein or amyloid beta inductive (alzheimer's disease) neuronal death, plays an important role.
P75
NTRAcceptor is also relevant with the Nogo acceptor, and relates to the inhibiting signal conduction of these myelin proteins at axon growth.Consequently, p75
NTRAcceptor plays significant feature in the adjusting of neuron plasticity and neurone-neuroglial interaction, thereby expression is used to promote the selection of the treatment target of neurotization.
Except nervous system disorders and neurodegenerative disease, also show p75
NTR(M.L.Bochaton-Pialat etc., Am.J.Pathol., 1995,146,1-6 can play a role in cardiovascular diseases such as atherosclerosis and myocardial ischemia etc.; H.Perlman, Circulation, 1997,95,981-987).Recently studies show that p75 in the atherosclerotic lesions (atherosclerosis lesion)
NTRAnd the expression of neurotrophin and the increase of popularity apoptosis (massive apoptosis).
Several researchs also hint p75
NTRBe medium (Rihl M. etc., the Ann.Rheum.Dis.2005:64 (11): 1542-9 of inflammation; Raychaudhuri S.P. etc., Prog.Brain.Res.2004; 146:433-7, Tokuoka S. etc., Br.J.Pharmacol.2001,134:1580-1586).
P75
NTRAlso in oncobiology, play a significant role.
Known multiple compound and trkA/NGF/p75
NTRInteraction takes place or has the activity of NGF (nerve growth factor) type in system.Therefore, patent application WO 00/59893 has described the pyrimidine derivatives that replaces, and the pyrimidine derivatives of described replacement has NGF type activity and/or increased NGF to the PC12 cell activity.
Patent application WO 03/104225 has described p75
NTRAcceptor shows the compound of avidity.The metabolism of height takes place in these compounds, and shows that the hERG gene (human Ether a go-go Related Gene) of high percent suppresses.
The K of hERG genes encoding potassium-channel
v11.1. albumen.Known this protein has effect to heart electroactive.When suppressing the ability of described passage conduction by the electric current of cytolemma through drug effect, can cause the fatal illness of potential, be called QT syndrome.Some medicines have suppressed this albumen, have also brought the concurrent sudden death risk as adverse side effect simultaneously.This make hERG suppress to become important topic in drug control and the medicament research and development (Sanguinetti MC, Tristani-Firouzi M (March 2006). " hERG potassium channels and cardiac arrhythmia " .Nature 440 (7083): 463-9).
Summary of the invention
Theme of the present invention is to p75
NTRThe new compound of the demonstration avidity of acceptor, it does not have the shortcoming that hypermetabolism that the prior art compound had and strong hERG suppress.Therefore, it demonstrates the advantage that is used for the development of new medicine.
Theme of the present invention is the compound corresponding to following formula (I):
Wherein,
-m is 0 or 1;
-A is:
And B is a hydrogen atom
Or
A is a hydrogen atom, and B is:
-R1 and R2, it can be identical or different, is hydrogen or halogen atom independently, C
1-C
4Alkyl, C
1-C
4Fluoroalkyl, C
1-C
2Perfluoroalkyl or C
1-C
4Alkoxyl group or trifluoromethoxy;
-n is 1 or 2;
-R3 is the group of following formula:
Wherein R4 and R5, it can be identical or different, is positioned at any available position, and be hydrogen or halogen atom independently, hydroxyl, C
1-C
4Alkyl, C
1-C
4Fluoroalkyl, C
1-C
2Perfluoroalkyl or C
1-C
4Alkoxyl group, trifluoromethoxy, cyano group or COOH, COO alkyl, CONH2, CONR6R7 or NHCOR group;
-R, R6 and R7 are C
1-C
6Alkyl.
Formula (I) compound can comprise one or more unsymmetrical carbons.Therefore they can be enantiomorph or diastereomer form.These enantiomorphs and diastereomer and mixture (comprising racemic mixture) constitute a part of the present invention.
Formula (I) compound can be alkali or with the form of the additive salt of acid.Such additive salt constitutes a part of the present invention.
These salt can use medicinal acid to prepare, but useful other sour salt that for example is useful on purifying or separate type (I) compound also is a part of the present invention.
In the context of the present invention:
-term " halogen atom " means: fluorine, chlorine, bromine or iodine;
-term " alkyl " means: the radical of saturated aliphatic group of straight chain or branching.For example, can mention C
1-C
4Alkyl, it can represent methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
-term " fluoroalkyl " means: the alkyl that wherein one or more hydrogen atoms have been replaced by fluorine atom;
-term " perfluoroalkyl " means: the alkyl that all replaced by fluorine atom of all hydrogen atoms wherein;
-term " alkoxyl group " means :-O-alkyl, wherein alkyl as defined above.
In formula (I) compound of theme of the present invention, another group compound is made of following, and wherein R4 and R5 can be identical or differently, are positioned at any available position, and are CONH independently
2, CONR6R7 or NHCOR, R, R6 and R7 are as defined above; Described compound is alkali or acid salt form.
In formula (I) compound of theme of the present invention, another group compound is made of formula (I) compound, wherein:
-m is 1;
-A is:
And B is a hydrogen atom;
-R1 and R2, it can be identical or different, is hydrogen or halogen atom independently, C
1-C
4Alkyl, C
1-C
4Fluoroalkyl, C
1-C
2Perfluoroalkyl or C
1-C
4Alkoxyl group or trifluoromethoxy;
-n is 1 or 2;
-R3 is the group of following formula:
Wherein R4 and R5 can be identical or differently, are positioned at any available position and independently for hydrogen or halogen atom, hydroxyl, C
1-C
4Alkyl, C
1-C
4Fluoroalkyl, C
1-C
2Perfluoroalkyl or C
1-C
4Alkoxyl group, trifluoromethoxy, cyano group or COOH or COO alkyl;
And it is the form of alkali or acid salt.
In formula (I) compound of theme of the present invention, another group compound is made of following compound, and wherein R1 is not H, and R2 as mentioned above;
And it is the form of alkali or acid salt.
In formula (I) compound of theme of the present invention, another group compound is made of following compound, wherein
R1 is at the 2-of phenyl, 3-or 4-position, and be halogen atom or more specifically, chlorine atom, or CF
3Group, and R2 is hydrogen or 3-or 4-halogen, more specifically, 3-or 4-Cl; Perhaps R1 is at 2-, 3-or 4-position, and be chlorine atom or CF
3Group, and R2 is a hydrogen atom; Perhaps R1 is in the 3-position of phenyl, and is CF
3Group, and R
2In the 4-position of phenyl, and be the chlorine atom; Perhaps R1 is in the 2-position of phenyl, and is the chlorine atom, and R2 is in the 3-position of phenyl, and is the chlorine atom; And/or
R3 is pyridine-2-base or pyrimidine-2-base, by R4 and R5 replace as defined above; And/or
n＝1；
And it is the form of alkali or acid salt.
In the compound of aftermentioned group, can mention following formula (I) compound, wherein:
R1 is 3-CF
3
R2 is a 4-chlorine;
R3 is 5-CF
3Pyridine-2-the base that replaces; And
n＝1；
And it is the form of alkali or acid salt.
In formula (I) compound of theme of the present invention, can mention following compound particularly:
-
Compound 1: 4-{2-[4-(4-chloro-3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 2: 4-{2-[4-(4-chloro-3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-picoline-2-yl) piperazine-2-ketone;
-
Compound 3: 4-{2-[4-(4-chloro-phenyl-)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 4: 4-{2-oxo-2-[4-(3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl] ethyl }-1-(pyridine-2-yl) piperazine-2-ketone;
-
Compound 5: 4-{2-[4-(4-chloro-3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(pyridine-2-yl) piperazine-2-ketone;
-
Compound 6: 4-{2-[4-(4-chloro-phenyl-)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(pyridine-2-yl)-piperazine-2-ketone;
-
Compound 7: 4-{2-[4-(2, the 3-dichlorophenyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 8: 4-{2-[4-(4-chloro-phenyl-)-3,6-dioxy-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(6-chloropyridine-2-yl) piperazine-2-ketone;
-
Compound 9: 4-{2-[4-(3-chloro-phenyl-)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 10: 4-{2-[4-(4-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 11: 4-{2-[4-(3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 12: 4-{2-[4-(4-chloro-3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-pyridin-3-yl piperazine-2-ketone;
-
Compound 13: 1-(6-chloropyridine-3-yl)-4-{2-[4-(4-chloro-3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl } piperazine-2-ketone;
-
Compound 14: 4-{2-oxo-2-[5-(3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl] ethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 15: 4-{2-oxo-2-[4-(3-Trifluoromethoxyphen-l)-3,6-dihydro-2H-pyridine-1-yl] ethyl }-1-(pyridine-2-yl) piperazine-2-ketone;
-
Compound 16: 4-{2-[4-(4-chloro-3-trifluoromethyl)-2,5-dihydro-pyrroles-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 17: 4-{2-[4-(3,5-two (trifluoromethyl) phenyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 18: 4-{2-[4-(3-aminomethyl phenyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 19: 4-{2-[4-phenyl-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 20: 4-{2-oxo-2-[5-(2, the 3-dichlorophenyl)-3,6-dihydro-2H-pyridine-1-yl] ethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 21: 4-{2-oxo-2-[5-(3-p-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-yl] ethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
And it is the form of alkali or acid salt.
Hereinafter, term " blocking group Pg " means becomes possible group below making: protective reaction functional group for example hydroxyl or amine between synthesis phase on the one hand, and the complete reactive functional groups of regeneration when end of synthesis on the other hand.The example of protecting group and guard method and deprotection method is at Protective Groups in Organic Synthesis, Green etc., 2nd edition (John Wiley ﹠amp; Sons, Inc., New York) in provide.
According to the present invention, general formula (I) compound can be according to following method preparation.
Scheme 1:
A wherein, B, m, n and R3 be formula (I) compound as defined above, can react according to method known to those skilled in the art as described in WO03/104225 by formula (IV) compound as defined above and formula V compound as defined above to prepare.More specifically, the method for preparing general formula (I) compound comprises with formula (IV) compound and logical formula V compound that in the presence of alkali react, its Chinese style (IV) compound is in the solvent described in the WO 03/104225
A wherein, B, m and n institute's definition in the general formula (I), and Hal represents halogen atom, chlorine for example and lead to the formula V compound is
Wherein R3 such as general formula (I) definition.Therefore, for alkali, can mention organic bases such as triethylamine, N, N-diisopropylamine, diisopropylethylamine (DPEA) or N-methylmorpholine, or alkaline carbonate or supercarbonate such as salt of wormwood, yellow soda ash or sodium bicarbonate, and exist or do not have alkaline metal iodide, as potassiumiodide or sodium iodide.Advantageously, be reflected at solvent such as acetonitrile, N, in dinethylformamide (DMF), N-N-methyl 2-pyrrolidone N-(NMP), toluene or the propan-2-ol, carry out in envrionment temperature to the temperature of solvent refluxing temperature.Term " envrionment temperature " means 5 to 25 ℃ temperature.Attempt an example, described reaction can be carried out in solvent such as DMF in the presence of sodium bicarbonate and sodium iodide.Described reaction is preferably carried out in microwave reactor.
In thus obtained general formula (I) compound, can modify R by the processing that those skilled in the art habitually practise, R1, R2, R4, R5, R6 and R7 for example obtain carboxyl by the ester hydrolysis group.
The acid salt of general formula (I) compound can obtain by formula (I) compound that suitable acid is added into free alkali form.
Wherein R1 and R2 are suc as formula defined formula (IV) compound in (I) compound, can by with formula (II) compound and formula (III) compound according to method known to those skilled in the art, for example, in the presence of alkali, in solvent, prepare as reacting as described in the WO03/104225.
More specifically, formula (IV) compound can obtain by corresponding formula (II) compound and formula (III) compound are reacted, and its Chinese style (II) compound is
A wherein, B and m in the general formula (I) definition; Be the acid salt form randomly, and formula (III) compound is
Wherein n and Hal be suc as formula defining in (IV), and Hal ' is halogen atom, and it can be identical or different with Hal.Preferably, Hal ' is the chlorine atom.
This reaction is normally at alkali such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine exist down, in the mixture of solvent such as methylene dichloride, chloroform, tetrahydrofuran (THF) Huo diox or these solvents, carries out to the temperature of envrionment temperature at 0 ℃.Formula (II) and (III) compound is normally commercially available, or can prepare according to method known to those skilled in the art.
Wherein R3 prepares according to method known to those skilled in the art suc as formula defined formula V compound in (I).For example, it can be according to following method preparation.
Scheme 2:
More specifically, the formula V compound can prepare from corresponding formula (XI) compound, and wherein R3 defines suc as formula (I) is middle, and Pg is the blocking group (as benzyl) of nitrogen-atoms.This reaction can be undertaken by the application or (adaptation) any method known to those skilled in the art of migrating; Usually, this reaction is in acidic medium, at catalyzer as carrying out in the presence of the Pd/C.
Formula (XI) compound can Pg be formula (VIII) compound of blocking group suc as formula defining in (I) by R3 wherein, acquisition in the presence of formula (VI) compound.Usually, this reaction is to carry out in envrionment temperature to the temperature that can wrap the boiling point of aqueous reaction mixture.
Perhaps, formula (XI) compound can from formula (IX) compound by with alkalimetal hydride inert solvent such as toluene, dimethyl formamide or methyl-sulphoxide, obtain in the thermotonus of envrionment temperature to the reaction mixture boiling point.
Formula (IX) but compound through type (VII) compound by with ethyl bromoacetate or ethyl chloroacetate at solvent such as butanols or acetone, in the presence of alkali such as salt of wormwood, obtain in the thermotonus of envrionment temperature to the reaction mixture boiling point.
Formula (VIII) compound can X be formula (VII) compound of halogen atom (as chlorine) suc as formula defining (I) from R3 wherein, and Pg is that formula (X) compound suc as formula defined blocking group in (VIII) exists down and obtains therein.Usually, this reaction is to carry out in envrionment temperature to the temperature of the boiling point of reaction mixture.
Randomly, method of the present invention comprises the steps, promptly separates the required product that obtains.
According to it on the other hand, theme of the present invention also is formula (IV) compound
A wherein, B, m and n in the general formula (I) definition, and Hal is a halogen atom, for example chlorine; And it is the form of alkali or acid salt.These compounds can be used as intermediate for synthesis type (I) compound.
For initial compounds in scheme 1 and 2 and reactant, if do not describe its preparation method, then it is commercially available, or is described in document, perhaps can be according to described method or method known to those skilled in the art prepare herein.
Following embodiment has described according to the present invention the preparation of some compound.These compounds not tool are limited, only are explanation the present invention.The numbering of illustrative compound be with reference to provide in the form hereinafter those, it shows the chemical structure and the physical properties of some compounds of the present invention.
HPLC is undertaken by the ThermoElectron LCQ Deca XP Max system that disposes ion trap mass spectrometry detector and diode-array detector.
The condition that is used for liquid chromatography-mass spectrography (LC/UV/MS) analysis is as follows:
-chromatographic system A
-eluent A=H
2O+0.01%TFA
-eluent B=CH
3CN
-gradient: the B of 98% A to 95%, 10 minutes, used 95% B wash-out 5 minutes then.
-flow velocity 0.5 ml/min; 40 ℃ of temperature
The concentration of-injection 2 μ l is that 0.1mg/ml is at CH
3CN: H
2O=9: the solution in 1 mixture
-chromatographic system B
-eluent A=H
2O+0.05%TFA
-eluent B=CH
3CN+0.035%TFA
-gradient: the B of 98% A to 95%, 12 minutes, used 95% B wash-out 3 minutes then.
-flow velocity 0.7 ml/min; 40 ℃ of temperature
The concentration of-injection 2 μ l is that 0.1mg/ml is at CH
3CN: H
2O=9: the solution in 1 mixture
-chromatographic system C
Eluent A=5mM ammonium acetate buffer, pH 6.5
Eluent B=CH
3CN
Gradient: the B of 98% A to 95%, 10 minutes, used 95% B wash-out 5 minutes then.
-flow velocity 0.5 ml/min; 40 ℃ of temperature
The concentration of-injection 2 μ l is that 0.1mg/ml is at CH
3CN: H
2O=9: the solution in 1 mixture
Product detects by UV at 220nm.
Used post is the C18 post, granularity between 2 and 4 μ m, preferred 3.5 μ m.
For the mass spectrum part:
-ionization mode: positive electron spray(ES) (API-ES polarity+)
-sweep limit: 120 to 1500uma.
Proton magnetic resonance (PMR) (
1H NMR) spectrum writes down under the following conditions:
A) disposing on the Bruker machine of Avance III supervisory control desk (console) at 500MHz;
B) disposing on the Bruker machine of Avance I supervisory control desk at 400MHz.
Chemical shift is write down with ppm with reference to the TMS frequency.
The abbreviation that is used for characterization signal is as described below: s=is unimodal, and bs=is wide unimodal, the m=multiplet, and the wide multiplet of bm=, d=is bimodal, and bd=is wide bimodal, t=triplet, q=quartet.
*=because the interference of the broad peak that causes of water and can not amassing.
*=because the interference at the peak that causes of NMR solvent and can not amassing.
Two partly overlapping peaks of 2Xm=.
Preparation 1
1-(5-5-flumethiazine-2-yl) piperazine-2-keto hydrochloride
10g 2-chloro-5-(trifluoromethyl) pyridine (formula (VIII) compound) and 40.5ml N-benzyl quadrol (formula (X) compound) were heated 6 hours in round-bottomed flask at 135 ℃.In mixture impouring water, and with the mixture ethyl acetate extraction of gained.Dry and the evaporate to dryness with the product of gained; Thus obtained crude product is passed through purification by flash chromatography.The isolating product of 14g (formula (VIII) compound) is dissolved in 200ml 2NHCl solution.Add 30g trimerization oxalic dialdehyde dihydrate (compound VI) and mixture was stirred 72 hours in envrionment temperature.It is used ethyl acetate extraction.Dry and the evaporate to dryness with the product of gained; Thus obtained crude product is passed through purification by flash chromatography.The isolating product of 10g (formula (IX) compound) is dissolved in 450ml ethanol, adds 15ml saturated aqueous isopropanol of HCl and the Pd/C of 3g 10% then.Make mixture under hydrogen stream 40 ℃ thermotonus 4 hours.The product of gained is filtered and evaporate to dryness, and obtain 3g title compound (formula V compound), fusing point 205-207 ℃.
Preparation 2
1-(5-picoline-2-yl) piperazine-2-keto hydrochloride
4.7g 2-chloro-5-picoline (formula (VII) compound) and 27.5ml N-benzyl quadrol (formula (X) compound) were heated 5 hours in round-bottomed flask at 135 ℃.With mixture impouring water, and with the mixture ethyl acetate extraction of gained.Dry and the evaporate to dryness with the product of gained; Thus obtained crude product is passed through purification by flash chromatography.The product (formula (VIII) compound) that has separated 3.6g.
This product of 1.5g is dissolved in the 3ml butanols.Add 0.85g salt of wormwood and 1.05g ethyl bromoacetate, then mixture was heated 3 hours at reflux temperature.With its impouring water and use ethyl acetate extraction.Dry and the evaporate to dryness with the product of gained; Thus obtained crude product is passed through purification by flash chromatography.Then the isolating product of 1g (formula (IX) compound) is dissolved in toluene, under nitrogen gas stream, this solution slowly is added into the solution of sodium hydride (NaH) in 25ml toluene of 0.25g 60% then.Mixture was heated 2 hours at reflux temperature.With its impouring water and with the mixture ethyl acetate extraction of gained.Dry and the vaporising under vacuum with the product of gained.
Obtain 0.6g crude product is the form (formula (IX) compound) with oily matter, it is dissolved in 25ml ethanol, add 1.5ml saturated aqueous isopropanol and the 0.3g 10%Pd/C of HCl then.Make mixture under hydrogen stream 40 ℃ thermotonus 4 hours.The product of gained is filtered and vaporising under vacuum, and the title compound (formula V compound) of acquisition 0.3g).
Preparation 3
2-chloro-1-[4-[3-trifluoromethyl-4-chloro-phenyl-]-1-[3,6-dihydro-1 (2H) pyridyl]]-the 1-ethyl ketone
With 4-[3-(trifluoromethyl)-4-chloro-phenyl-]-3,6-dihydro-1 (2H)-pyridine hydrochloride (formula (II) compound) (3.94g) is cooled to 0 ℃ with 3.8ml triethylamine/33.5ml methylene dichloride.Dropwise add 2-chloroacetyl chloride (formula (III) compound), and mixture was stirred 1 hour 30 minutes.Add water, and with the mixture of dichloromethane extraction gained.With organic phase Na
2SO
4Drying, and vaporising under vacuum.
Obtain the compound (formula (IV) compound) of 4.2g amorphous solid
Embodiment 1:
Compound 1:4-{2-[4-(4-chloro-3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone and hydrochloride thereof
The compound (0.49mg) of preparation 3, compound (0.4mg), salt of wormwood (0.41g) and the mixture of sodium iodide (0.45g) in the 7ml dimethyl formamide of preparation 1 were heated 30 minutes at 180 ℃ in microwave reactor.With reaction mixture impouring water, and with the mixture of ethyl acetate extraction gained.With organic phase Na
2SO
4Drying is filtered and evaporation, obtains the crude product of 700mg oily matter form.By the silica gel chromatography product, its mixture with cyclohexane/ethyl acetate=1/1 carries out wash-out.Its hydrochloride is by adding the formulations prepared from solutions of hydrochloric acid in Virahol.Obtained the title compound of 200g.
M+H
+＝m/z?547
δ(ppm，dmso-d6)：2.55(bs，**)；2.63(m，**)；3.43-3-54(m，2H)；3.65(m，*)；3.75(m，1H)；3.96(bs，2H)；4.18(m，6H)；6.40(bs，1H)；7.72(d，J＝8.4Hz，1H)，7.74-7.80(m，1H)，7.80-7.85(m，1H)，8.21(d，J＝9Hz，1H)；8.26(dd，J
1＝9Hz，J
2＝2Hz，1H)；8.88(s，1H)。
Embodiment 2:
Compound 2:4-{2-[4-(4-chloro-3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-picoline-2-yl) piperazine-2-ketone and hydrochloride thereof
Title compound is by carrying out embodiment 1 described method, but is to use the compound of preparation 2 to replace the compound of preparation 1 to obtain.
M+H
+＝m/z?493
(machine is a). δ (ppm, dmso-d6): 2.32 (s, 3H), 2.56 (m, 1H), 2.65 (m, 1H), 3.10-3.60 (m, *), 3.64 (m, 1H), 3.77 (m, 1H), 3.98 (m, 2H), 4.05-4.51 (m, 6H), 6.41 (m, 1H), 7.69 (dd, J=8.4 and 2.0Hz, 1H), 7.73 (d, 8.5Hz, 1H), and 7.75-7.81 (m, 2H), 7.83 (bd, J=9.3Hz, 1H), 8.31 (bd, J=2Hz, 1H);
Following table has shown chemical structure and the physical properties of some embodiment of The compounds of this invention.In this table:
In " salt " hurdle, the compound of "-" expression free alkali form, and the compound of " HCl " expression hydrochloric acid form.
Table
The compounds of this invention is the theme of following biochemical research.
Cell cultures:
Wrapping by the culturing bottle of collagen (Becton Dickinson, France) conventional cultivation SH-SY-5Y strain (human neuroblastoma) in, substratum be the DMEM substratum (Dulbecco ' s Modified Eagle ' s Medium, Gibco BRL, France), its contain 5%FCS (foetal calf serum) (Boehringer Mannheim, Germany), Sodium.alpha.-ketopropionate (1mM) and glutamine (4mM).
Conventional Bep 75 clones (SK-N-BE Bep 75) that cultivate parental plant SK-N-BE (human neuroblastoma) and the complete type of stably express people p75NTR acceptor, substratum is the RPMI substratum, and it contains FCS (5%), Sodium.alpha.-ketopropionate (1mM) and glutamine (4mM).For SK-N-BE Bep 75 cells, add Totomycin (200 μ l/20ml substratum) as selective agent.
125I NGF and p75
NTRThe research of receptors bind
According to Weskamp (Neuron, 1991,6,649-663) described method, to the cell suspension of SK-N-BE Bep 75 strains carry out NGF in conjunction with research (nerve growth factor iodine-125 radio-labeled, Amersham-2000Ci/mmol).After 37 ℃ are cultivated 1 hour in advance, sum up incompatible definite non-specific binding by measuring at cell in the presence of the not radiolabeled NGF (1 μ M).Calculating specificity from the difference of total binding measurement and non-specific binding measurement combines.The iodate NGF of employing concentration 0.3nM (
125I NGF) being at war with property experiment.The compounds of this invention is right
125I NGF and p75
NTRReceptors bind 50% inhibition concentration (IC
50) very low, be 10
-6To 10
-11M.
In this test, formula (I) compound presents activity, IC
50Value is 10
-6To 10
-11M.
For example, compound 3 and 1 shows the IC of 0.1nM and 5.2nM
50
Be independent of the p75 of its part
NTRThe dimerization research of acceptor
Cell suspension to SK-N-BE Bep 75 strains carries out p75
NTRReceptor dimerization research.With cell (2.5 * 10
4Individual cells/well) place each holes of 96 orifice plates, place 24h, then under the situation that has or do not exist The compounds of this invention 37 ℃ of pre-cultivations 1 hour.Add then by cultivation and derive from the supernatant liquor (ultimate density 10nM) that HEK293 people's cell of kidney obtains, the described HEK293 people's cell that derives from kidney is expressed justacrine and alkaline phosphatase link coupled p75 in transfection after 48 hours
NTRThe solvable type of acceptor (born of the same parents' outside part of this receptor).Solvable p75
NTRThe specificity bonded of the acceptor that exists on acceptor and SK-N-BE Bep 75 cells is quantitatively determined by following method: cultivate cell after 1 hour at 37 ℃ in the presence of described supernatant liquor, measure the alkaline phosphatase enzymic activity.After filtering and being transferred to filter membrane on 24 orifice plates, (promptly usefulness Roche) is measured alkaline phosphatase activities by adding the CDP-Star chemical luminous substrate.The compounds of this invention is to p75
NTR50% inhibition concentration (IC of receptor dimerization
50) very low, be 10
-6To 10
-11M.
For example, compound 1,2 and 3 shows the IC of 1.34nM, 3.88nM and 0.11nM respectively
50
Apoptotic measurement
In the culture dish (Biocoat collagen I) of diameter 35mm, add cell (10
5Individual cells/well) (human neuroblastoma strain SH-SY-5Y and SK-N-BE Bep 75) cultivated 24 hours in comprising the suitable culture medium of 5%FCS.Remove substratum then, with PBS (phosphate-buffered saline of Dulbecco) drip washing, then adding contains the fresh culture of 5%FCS or contains NGF (concentration is 10ng/ml) or the substratum of beta-amyloyd peptide (A β 1-40) (concentration is 10 μ M) under the situation that has or do not exist The compounds of this invention.In treatment S H-SY-5Y strain after 48 hours and treatment S K-N-BE Bep 75 strains after 24 hours, by the kytoplasm histone that quantitatively combines with dna fragmentation measure the apoptosis level (necrocytosis detection ELISA, Boehringer Mannheim, Germany).Apoptotic water-glass is shown per 10
5The amount of the oligomerization nucleosome of individual cell.Each value is corresponding to the mean value that is distributed in 9 experimental points in three independent experiments.
Formula (I) compound presents and suppresses the apoptosis-induced activity of NGF, IC
50Value is 10
-6To 10
-11M.For example, compound 1 shows the IC of 1.61nM
50And compound 5 shows the IC of 52nM
50
Therefore, The compounds of this invention and p75
NTRThe combination of acceptor shows as: one side suppresses the neurotrophin inductive or is independent of the receptor dimerizationization of described part on the biological chemistry level, suppress p75 on the other hand on cell levels
NTRReceptor-mediated apoptosis-promoting effect.
Therefore, according to a theme of the present invention, formula (I) compound exhibits is to being independent of the p75 of its part
NTRIt is active that receptor dimerizationization very advantageously suppresses.
Therefore, The compounds of this invention can be used for preparing medicine, is specially to be used for prevention or to treat any p75 of relating to
NTRThe medicine of the pathological state of acceptor.
Therefore, according to a further aspect in the invention, theme of the present invention is the medicine that comprises the additive salt of formula (I) compound or itself and medicinal acid.
According to a further aspect in the invention, theme of the present invention is the additive salt of formula (I) compound or itself and medicinal acid, is used to prevent or treat following pathological state.
Therefore, The compounds of this invention is used among the human or animal, treats or prevent various p75
NTRDependent conditions, for example maincenter or peripheral nerve degenerative disease such as senile dementia (senile dementia), epilepsy (epilepsy), alzheimer's disease (Alzheimer ' s disease), Parkinson's disease (Parkinson ' s disease), Huntington Chorea (Huntington ' s chorea), mongolism (Down ' s syndrome), prion disease (prion diseases), amnesia (amnesia), schizophrenia (schizophrenia), dysthymia disorders (depression), bipolar disorder (bipolar disorder); Amyotrophic lateral sclerosis (amyotrophic lateral sclerosis), multiple sclerosis (multiple sclerosis); Cardiovascular disorder (cardiovascular conditions) is as heart and injury behind the ischemic (post-ischaemic cardiac damage), myocardosis (cardiomyopathies), myocardial infarction (myocardial infarction), (heart failure), heart ischemia (cardiac ischaemia) in heart failure, cerebral infarction (cerebral infarction); Peripheral neurophaty (peripheral neuropathies) (diabetic, traumatic or iatrogenic); Optic nerve injury and retina injury (damage to the optic nerve and to the retina) (retinitis pigmentosa (retinal pigment degeneration), glaucoma (glaucoma)); Retinal ischemia (retinal ischaemia); Macular degeneration (macular degeneration); Notochord wound (spinal chord traumas) and cranium wound (cranial traumas); Atherosclerosis (atherosclerosis); Narrow (stenoses); Healing obstacle (healing disorder); Alopecia (alopecia).
The compounds of this invention also can be used for treating cancer such as lung cancer, thyroid carcinoma, carcinoma of the pancreas, prostate cancer, carcinoma of small intestine and colorectal carcinoma or mammary cancer, and is used for the treatment of tumour, transfer and leukemia (leukaemias).
The compounds of this invention also can be used for treating respiratory system disease such as pneumonia (pulmonary inflammation), transformation reactions (allergy) and asthma (asthma), perhaps chronic obstructive pulmonary disease (chronic obstructive pulmonary disease).
The compounds of this invention also can be used for treating skin pain (cutaneous pain) (skin, subcutis and relevant organ), somatalgia (somatic pain), visceral pain (visceral pain) (in the recycle system, respiratory system, gastro-intestinal system or the urogenital system), and neuralgia (neurological pain).
The compounds of this invention also can be used for treating chronic nervosa and inflammatory pain (chronic neuropathic and inflammatory pain), and treatment autoimmune disease (autoimmune diseases) is as rheumatoid arthritis (rheumatoid arthritis).
The compounds of this invention also can be used for treating disease for example spondylarthritis,ankylosing (ankylosing spondyl arthritis), psoriatic arthritis (psoriatic arthritis) or plaque psoriasis (plaque psoriasis).
The compounds of this invention also can be used for treatment fracture (bone fracture), perhaps treats or prevent for example osteoporosis (osteoporosis) of osteopathy (bone diseases).
Therefore, theme of the present invention is that formula of the present invention (I) compound is used for prevention or treats any p75 of relating to
NTRThe pathological state of acceptor more specifically is above-mentioned pathological state.
According to a further aspect of the present invention, the present invention relates to pharmaceutical composition, it comprises the The compounds of this invention as activeconstituents.These pharmaceutical compositions contain at least a The compounds of this invention of effective dose or the pharmaceutical salts and at least a pharmaceutical excipient of described compound.
According to medicament forms and required medication, described vehicle is selected from usual excipients well known by persons skilled in the art.
The pharmaceutical composition of the present invention of administration in being used for oral administration, sublingual administration, subcutaneous administration, intramuscular administration, intravenous administration, surperficial administration, topical, tracheae, intranasal administration, percutaneous dosing or rectal administration, above-mentioned formula (I) activeconstituents or its salt can be administered to animal and human's class to prevent or to treat above-mentioned illness or disease by unit form of medication (with the mixture of conventional medicine vehicle).
Suitable unit form of medication comprises oral administration form (for example tablet, hard capsule or soft capsule, powder agent, granule and oral solution or suspensoid), sublingual administration form, contains form of medication, eye drops form, intranasal administration form, inhalation form, topical form, parenteral (as through skin) form of medication, subcutaneous administration form, intramuscular administration form, intravenous administration form, rectal administration form and implant in clothes form of medication, the tracheae.With regard to topical, The compounds of this invention can be used in ointment, gelifying agent, ointment or the lotion.
For example, the unit form of medication of the The compounds of this invention of tablet form can comprise following component:
The compounds of this invention 50.0mg
N.F,USP MANNITOL 223.75mg
Croscarmellose sodium 6.0mg
W-Gum 15.0mg
Vltra tears 2.25mg
Magnesium Stearate 3.0mg
The dosage of the activeconstituents of administration every day can reach 0.01 to 100mg/kg, takes in one or many, and preferred 0.02 to 50mg/kg.Generally speaking, the per daily dose of The compounds of this invention can be the subliminal dose that this compound can produce result of treatment.
Higher dosage or may be suitable with regard to particular case than low dosage; Such dosage does not deviate from context of the present invention.According to conventional practice, the dosage that is suitable for every patient is determined with response according to medication and described weight in patients by the doctor.
According to a further aspect of the present invention, the invention still further relates to the method for the above-mentioned pathological state of treatment, described method comprises to the The compounds of this invention of patient's administration effective dose or its pharmaceutical salts.
Claims (15)
1. formula (I) compound of alkali form or acid salt form
Wherein,
-m is 0 or 1;
-A is:
And B is a hydrogen atom
Or
A is a hydrogen atom, and B is:
-R1 and R2, it can be identical or different, is hydrogen or halogen atom independently, C
1-C
4Alkyl, C
1-C
4Fluoroalkyl, C
1-C
2Perfluoroalkyl or C
1-C
4Alkoxyl group or trifluoromethoxy;
-n is 1 or 2;
-R3 is the group of following formula:
Wherein R4 and R5, it can be identical or different, is positioned at any available position, and be hydrogen or halogen atom independently, hydroxyl, C
1-C
4Alkyl, C
1-C
4Fluoroalkyl, C
1-C
2Perfluoroalkyl or C
1-C
4Alkoxyl group, trifluoromethoxy, cyano group or COOH, COO alkyl, CONH
2, CONR6R7 or NHCOR group;
-R, R6 and R7 are C
1-C
6Alkyl.
2. the compound of the alkali form of claim 1 or acid salt form, wherein R4 and R5 can be identical or differently, are positioned at any available position, and are CONH independently
2, CONR6R7 or NHCOR.
3. the compound of the alkali form of claim 1 or acid salt form, wherein:
-m is 1;
-A is:
And B is a hydrogen atom;
-R1 and R2, it can be identical or different, is hydrogen or halogen atom independently, C
1-C
4Alkyl, C
1-C
4Fluoroalkyl, C
1-C
2Perfluoroalkyl or C
1-C
4Alkoxyl group or trifluoromethoxy;
-n is 1 or 2;
-R3 is the group of following formula:
Wherein R4 and R5 can be identical or differently, are positioned at any available position and independently for hydrogen or halogen atom, hydroxyl, C
1-C
4Alkyl, C
1-C
4Fluoroalkyl, C
1-C
2Perfluoroalkyl or C
1-C
4Alkoxyl group, trifluoromethoxy, cyano group or COOH or COO alkyl.
4. the compound of the alkali form of aforementioned each claim or acid salt form, wherein R1 is not H.
5. the compound of the alkali form of aforementioned each claim or acid salt form, wherein R1 is at 2-, 3-or 4-position, and be chlorine atom or CF
3Group, and R2 is hydrogen or 3-or 4-Cl.
6. the compound of the alkali form of aforementioned each claim or acid salt form, wherein R3 is pyridine-2-base or pyrimidine-2-base, replaces by defined R4 of claim 1 and R5.
7. the compound of the alkali form of aforementioned each claim or acid salt form, wherein n=1.
8. aforementioned claim 1 and 3 to 7 each the alkali form or the compound of acid salt form, wherein
R1 is 3-CF
3
R2 is a 4-chlorine;
R3 is 5-CF
3Pyridine-2-the base that replaces; And
n＝1。
9. the compound of the alkali form of aforementioned each claim or acid salt form is selected from
Compound 1: 4-{2-[4-(4-chloro-3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
Compound 2: 4-{2-[4-(4-chloro-3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-picoline-2-yl) piperazine-2-ketone;
Compound 3: 4-{2-[4-(4-chloro-phenyl-)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
Compound 4: 4-{2-oxo-2-[4-(3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl] ethyl }-1-(pyridine-2-yl) piperazine-2-ketone;
Compound 5: 4-{2-[4-(4-chloro-3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(pyridine-2-yl) piperazine-2-ketone;
Compound 6: 4-{2-[4-(4-chloro-phenyl-)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(pyridine-2-yl)-piperazine-2-ketone;
Compound 7: 4-{2-[4-(2, the 3-dichlorophenyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
Compound 8: 4-{2-[4-(4-chloro-phenyl-)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(6-chloropyridine-2-yl) piperazine-2-ketone;
Compound 9: 4-{2-[4-(3-chloro-phenyl-)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
Compound 10: 4-{2-[4-(4-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
Compound 11: 4-{2-[4-(3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
Compound 12: 4-{2-[4-(4-chloro-3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-pyridin-3-yl-piperazine-2-ketone;
Compound 13: 1-(6-chloropyridine-3-yl)-4-{2-[4-(4-chloro-3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl } piperazine-2-ketone;
Compound 14: 4-{2-oxo-2-[5-(3-trifluoromethyl)-3,6-dihydro-2H-pyridine-1-yl] ethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
Compound 15: 4-{2-oxo-2-[4-(3-Trifluoromethoxyphen-l)-3,6-dihydro-2H-pyridine-1-yl] ethyl }-1-(pyridine-2-yl) piperazine-2-ketone;
Compound 16: 4-{2-[4-(4-chloro-3-trifluoromethyl)-2,5-pyrrolin-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 17: 4-{2-[4-(3,5-two (trifluoromethyl) phenyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 18: 4-{2-[4-(3-aminomethyl phenyl)-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 19: 4-{2-[4-phenyl-3,6-dihydro-2H-pyridine-1-yl]-the 2-oxoethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 20: 4-{2-oxo-2-[5-(2, the 3-dichlorophenyl)-3,6-dihydro-2H-pyridine-1-yl] ethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone;
-
Compound 21: 4-{2-oxo-2-[5-(3-p-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-yl] ethyl }-1-(5-5-flumethiazine-2-yl) piperazine-2-ketone.
10. the method for preparing formula (I) compound of aforementioned each claim, A wherein, B, m, n, R3 comprise the step that formula (IV) compound and logical formula V compound are reacted as defined above in the presence of alkali, its Chinese style (IV) compound is
A wherein, B, m and n in the general formula (I) definition, and Hal represents halogen atom,
And logical formula V compound is
Wherein R3 such as general formula (I) definition.
11. the formula of alkali form or acid salt form (IV) compound
A wherein, B, m and n such as claim 1 to 9 in each definition, and Hal is a halogen atom, but described compound is not 2-chloro-1-[4-(2-p-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-yl]-ethyl ketone and 2-chloro-1-[4-(4-bromophenyl)-3,6-dihydro-2H-pyridine-1-yl] ethyl ketone.
12. medicine is characterized in that it comprises in the claim 1 to 9 each formula (I) compound or the additive salt of this compound and medicinal acid.
13. pharmaceutical composition is characterized in that it comprises in the claim 1 to 9 each formula (I) compound or its pharmaceutical salts, and at least a pharmaceutical excipient.
14. each compound in the claim 1 to 9, it is used to prepare the medicine that is used to prevent or treat following disease: heart and injury, myocardosis, myocardial infarction, heart failure, heart ischemia, cerebral infarction behind maincenter or peripheral nerve degenerative disease, senile dementia, epilepsy, alzheimer's disease, Parkinson's disease, Huntington Chorea, mongolism, prion disease, amnesia, schizophrenia, dysthymia disorders, bipolar disorder, amyotrophic lateral sclerosis, multiple sclerosis, cardiovascular disorder, the ischemic; Peripheral neurophaty, optic nerve injury and retina injury, retinitis pigmentosa, glaucoma, retinal ischemia, macular degeneration, notochord wound, cranium wound, atherosclerosis; Narrow, cicatrization obstacle, alopecia, cancer, tumour, transfer, leukemia, respiratory system disease, pneumonia, transformation reactions, asthma, chronic obstructive pulmonary disease, skin pain, somatalgia, visceral pain and neuralgia, chronic nervosa and inflammatory pain, autoimmune disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, fracture, osteopathy and osteoporosis.
15. the compound of claim 14, it has inhibition and is independent of p75
NTRThe p75 of receptors ligand
NTRThe ability of receptor dimerizationization.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0803298 | 2008-06-13 | ||
| FR0803298A FR2932481B1 (en) | 2008-06-13 | 2008-06-13 | 4- {2-4-PHENYL-3,6-DIHYDRO-2H-PYRIDIN-1-YL] -2-OXO-ALKYL} -1-PIPERAZIN-2-ONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE. |
| PCT/FR2009/051117 WO2009150387A1 (en) | 2008-06-13 | 2009-06-12 | Derivatives of 2-oxo-alkyl-1-piperazin-2-one, preparation method thereof and therapeutic use of same |
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| AT (1) | ATE535524T1 (en) |
| AU (1) | AU2009259120B2 (en) |
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| CY (1) | CY1112417T1 (en) |
| DK (1) | DK2310383T3 (en) |
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| ES (1) | ES2378380T3 (en) |
| FR (1) | FR2932481B1 (en) |
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| HR (1) | HRP20120187T1 (en) |
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| JO (1) | JO2773B1 (en) |
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| NZ (1) | NZ589842A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2932481B1 (en) | 2008-06-13 | 2010-10-08 | Sanofi Aventis | 4- {2-4-PHENYL-3,6-DIHYDRO-2H-PYRIDIN-1-YL] -2-OXO-ALKYL} -1-PIPERAZIN-2-ONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE. |
| FR2932482B1 (en) * | 2008-06-13 | 2010-10-08 | Sanofi Aventis | NOVEL (PHENYL-3,6-DIHYDRO-2H-PYRIDINYL) - (PIPERAZINYL PONTE) -1-ALKANONE DERIVATIVES AND THEIR USE AS P75 INHIBITORS |
| FR2953836B1 (en) | 2009-12-14 | 2012-03-16 | Sanofi Aventis | NOVEL DERIVATIVES (HETEROCYCLE-TETRAHYDRO-PYRIDINE) - (PIPERAZINYL) -1-ALKANONE AND (HETEROCYCLE-DIHYDRO-PYRROLIDINE) - (PIPERAZINYL) -1-ALKANONE AND THEIR USE AS INHIBITORS OF P75 |
| FR2953839A1 (en) | 2009-12-14 | 2011-06-17 | Sanofi Aventis | NOVEL (HETEROCYCLE-PIPERIDINE CONDENSEE) - (PIPERAZINYL) -1ALCANONE OR (HETEROCYCLE-PYRROLIDINE CONDENSED) - (PIPERAZINYL) -1ALCANONE DERIVATIVES AND THEIR USE AS INHIBITORS OF P75 |
| EP2606894A1 (en) | 2011-12-20 | 2013-06-26 | Sanofi | Novel therapeutic use of p75 receptor antagonists |
| EP2950095B1 (en) | 2014-05-28 | 2018-08-29 | Technische Universität Dresden | Cell-based assay and screening methods for modulators of p75NTR signaling |
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